Gold nanoparticles decorated with monosaccharides and sulfated ligands as potential modulators of the lysosomal enzyme N-acetylgalactosamine-6-sulfatase (GALNS)

N-Acetylgalactosamine-6-sulfatase (GALNS) is an enzyme whose deficiency is related to the lysosomal storage disease Morquio A. For the development of effective therapeutic approaches against this disease, the design of suitable enzyme enhancers (i.e. pharmacological chaperones) is fundamental. The natural substrates of GALNS are the glycosaminoglycans keratan sulfate and chondroitin 6-sulfate, which mainly display repeating units of sulfated carbohydrates. With a biomimetic approach, gold nanoparticles (AuNPs) decorated with simple monosaccharides, sulfated ligands (homoligand AuNPs), or both monosaccharides and sulfated ligands (mixed-ligand AuNPs) were designed here as multivalent inhibitors of GALNS. Among the homoligand AuNPs, the most effective inhibitors of GALNS activity are the beta-D-galactoside-coated AuNPs. In the case of mixed-ligand AuNPs, beta-D-galactosides/sulfated ligands do not show better inhibition than the beta-D-galactoside-coated AuNPs. However, a synergistic effect is observed for alpha-D-mannosides in a mixed-ligand coating with sulfated ligands that reduced IC50 by one order of magnitude with respect to the homoligand alpha-D-mannoside-coated AuNPs. SAXS experiments corroborated the association of GALNS with beta-D-galactoside AuNPs. These AuNPs are able to restore the enzyme activity by almost 2-fold after thermal denaturation, indicating a potential chaperoning activity towards GALNS. This information could be exploited for future development of nanomedicines for Morquio A. The recent implications of GALNS in cancer and neuropathic pain make these kinds of multivalent bionanomaterials of great interest towards multiple therapies.

Automated summary

In this study, gold nanoparticles decorated with monosaccharides or sulfated ligands were designed as multivalent inhibitors for the enzyme GALNS associated with Morquio A. The beta-D-galactoside-coated AuNPs showed the most effective inhibition of GALNS activity. In the case of mixed-ligand AuNPs, alpha-D-mannosides exhibited a synergistic effect with sulfated ligands, leading to significantly stronger inhibition of GALNS.